Methemoglobinemia

Audience The targeted audience for this simulation are emergency medicine providers, including residents as well as advanced practice providers, to properly educate on recognizing, diagnosing, and managing methemoglobinemia. Introduction Methemoglobinemia is a blood disorder characterized by the presence of ferric form of hemoglobin in the blood. This form of hemoglobin can carry oxygen but is unable to release it effectively causing a range of symptoms including headache, dizziness, nausea, and cyanosis. It is rarely congenital and mostly caused by the exposure to oxidizing agents, such as local anesthetics and quinolones.1 Normally, oxygen can bind to hemoglobin while it is in the ferrous state (Fe2+). In cases of methemoglobinemia, the heme iron configuration is converted from ferrous (Fe2+) to ferric (Fe3+), making it unable to bind to oxygen. As a result, normal ferrous hemes experience an increased affinity for oxygen causing a leftward shift in the oxygen dissociation curve. This in turn causes functional anemia due to reduced oxygen carrying capacity.1 Methemoglobinemia can result from exposure to different medications as well as environmental factors and presents like other disease processes including chronic obstructive pulmonary disease exacerbations. Congenital methemoglobinemia due to cytochrome b5 reductase deficiency is very rare, but the actual incidence is not known. Increased frequency of disease has been found in Siberian Yakuts, Athabaskans, Eskimos, and Navajo.2 Although it is also an unusual occurrence, acquired methemoglobinemia is much more frequently encountered than the congenital form.1 In a 10-year retrospective study looking at the incidence rate of topical anesthetic-induced methemoglobinemia, it was found that the overall prevalence was 0.035%. A major risk factor was hospitalization at the time of a procedure being performed. An increased risk was also seen with benzocaine-based anesthetics.3 Educational Objectives At the end of this simulation case, participants should be able to: 1) recognize shortness of breath, cyanosis and respiratory distress, and the difference between all of them based on the clinical presentation 2) identify the underlying cause of the condition by conducting a thorough history and physical 3) know how to identify and treat methemoglobinemia by ordering necessary labs and interventions and understand the pathophysiology leading to methemoglobinemia 4) recognize patient’s response to treatment and continue to reassess. Educational Methods This is a high-fidelity simulation case that allows participants to evaluate and treat methemoglobinemia in a safe environment. The case is followed by a debriefing and small group discussion to review patient care skills, medical knowledge, interpersonal communication, practice-based learning, and improvement. Research Methods The educational content and efficacy were evaluated by oral feedback and a debriefing session immediately after completion of the simulation. A 5-point Likert scale was sent out to participants pre-simulation and post-simulation. Questions on the survey included whether they felt confident in their ability to recognize methemoglobinemia, understood the physiology and causes of methemoglobinemia, and felt confident in their ability to treat methemoglobinemia. Results Sixteen learners responded to the survey, consisting of EM residents and medical students. Post simulation, approximately 92% of EM residents answered agree or strongly agree in their ability to recognize and treat methemoglobinemia compared to pre-sim survey of about 62.5%. Post-simulation feedback also resulted in positive reception, and learners found it useful to run through an uncommonly seen case in the hospital. Results showed overall improvement in recognition and treatment of methemoglobinemia among residents and medical students. Discussion This simulation improved recognition of methemoglobinemia including signs and symptoms associated with it. Proper management and treatment options were included such as administration of methylene blue. Overall, this simulation was helpful in teaching EM residents how to recognize, manage, and treat methemoglobinemia. In addition, post-simulation debriefing allowed further discussion among residents, which they found valuable. Topics Methemoglobinemia, shortness of breath, cyanosis, respiratory distress, anemia, methemoglobin, oxygen dissociation curve, emergency medicine simulation.


Linked objectives and methods:
It is important for emergency medicine physicians to use this high-fidelity simulation method to quickly diagnose methemoglobinemia and provide an appropriate treatment plan. Methemoglobinemia requires a high index of suspicion and presents similar to other common complaints we see in emergency medicine. Learners will need to recognize that the patient is in respiratory distress and cyanotic (Objective 1). They will need to obtain a detailed medical/surgical history and perform in-depth physical exam to recognize acrocyanosis, which will help them find the underlying cause (Objective 2). The patient's past medical history of deep vein thromboses (DVTs) will distract the learner and may delay appropriate treatment. Appropriate diagnostic labs will need to be ordered, specifically Co-oximetry, which will lead the learner to the correct diagnosis of methemoglobinemia (Objective 3). If learners can recognize that the patient is presenting with methemoglobinemia, they will need to be able to treat it appropriately. Methemoglobinemia patients do not respond to supplementary oxygen and may deteriorate if the learner is unable to recognize it early on. Learner will need to order the appropriate intervention, such as methylene blue, for the patient to improve and will continue to reassess (Objective 4).

Results and tips for successful implementation:
This case was made for a high-fidelity simulation scenario to allow learners to recognize and treat methemoglobinemia. This simulation was used on emergency medicine interns and residents. Learners were assessed during the simulation and given graded percentages, which were later discussed during the debriefing session. Attending EM physicians were used during this simulation to evaluate learners' performance. There was also a senior resident in the room acting as a confederate to help move the case along. It is recommended to provide a pre-simulation survey as well as a post-simulation survey to get a baseline reading of where learners are at. During our simulation, 16 EM residents responded to both a pre-simulation as well as a post-simulation survey consisting of 6 questions on a 5-point Likert scale (questions included below). Post simulation, approximately 92% of EM residents (12 learners) answered agree or strongly agree in their ability to recognize and treat methemoglobinemia compared to pre-sim survey of about 62.5% (10 learners). Post-simulation feedback also resulted in positive reception and learners found it useful to run through an uncommonly seen case in the hospital. 10 medical students also responded to our survey. Results showed overall improvement in recognition and treatment of methemoglobinemia among residents and medical students. Overall feedback from learners and instructors was positive. This was measured using pre-and post-simulation surveys asking about the learners' ability to differentiate between ventilation and oxygenation. They were also asked about their ability to recognize and treat methemoglobinemia. Lastly, learners were surveyed about their ability to explain methemoglobinemia to a patient. Background and brief information: 55-year-old male patient brought into the emergency department via EMS from home in respiratory distress and complaining of shortness of breath, chills, lightheadedness, headache, and palpitations that have been going on for a few hours.

References
Initial presentation: Patient is in respiratory distress with mild wheezing on exam and coughing. Acrocyanosis is appreciated as well.
How the scene unfolds: Patient presents to the emergency department with respiratory distress. Participants should place patient on oxygen and obtain vitals while taking history.
While taking history, participant should ask about any surgical history, and the patient will inform them that he had a dental procedure done earlier that morning and had 20% benzocaine used during treatment. Patient's oxygen saturation should stay constant at 85% along with mild wheezing and a cough. These symptoms will distract the participant and drag him toward underlying COPD that the patient has. In addition, patient will have acrocyanosis, which should guide towards a correct diagnosis. Participant should perform a physical exam, specifically cardiovascular and pulmonary. Labs, ECG, and imaging might be ordered at this time along with a breathing treatment. Participant should attempt to use BiPAP, which will not help his condition. Patient's tachycardia will continue to worsen as well as his tachypnea. His hypoxia will not improve and will only worsen if learner does not recognize methemoglobinemia. A nurse confederate may guide the learner and inform him that the patient's blood appears "chocolate colored." If participant suspects methemoglobinemia, cooximetry should be ordered to correctly identify methemoglobinemia. After participant identifies methemoglobinemia, methylene blue should be ordered and a repeat MetHb should be ordered. Failure to correctly identify methemoglobinemia will cause the patient to become confused and suffer a seizure. Patient will eventually go into respiratory arrest if methemoglobinemia is not recognized. Patient is tachycardic and in respiratory distress.
Airway intact. Physical exam shows mild wheezing bilaterally along with cyanotic fingertips. He does appear anxious. When the patient is placed on non-rebreather mask and given breathing treatment, proceed to next step. If patient is not placed on a non-rebreather mask within 3 minutes, RR will increase to 30 with HR increasing to 125 bpm. Patient should be speaking 2-3-word sentences but is otherwise awake and alert. Labs can be ordered in this step. Do not continue to next step if supplementary oxygen is not ordered. If the learner completely fails to order labs and/or place patient on supplementary oxygen, nurse in the room or RT may bring it to their attention that the patient is exhibiting acrocyanosis and is hypoxic. Methemoglobinemia has two primary causes, acquired and congenital. Although it is also an unusual occurrence, acquired methemoglobinemia is much more frequently encountered than the congenital form. 1 Most commonly, it is caused by ingestion or skin exposure to an oxidizing agent, such as benzocaine and/or other local anesthetics. 4 It can also be caused by nitrites, nitrates, quinolones, antimalarials, or Dapsone. 5 In a 10-year retrospective study looking at the incidence rate of topical anesthetic-induced methemoglobinemia, it was found that the overall prevalence was 0.035%. A major risk factor was hospitalization at the time of a procedure being performed. An increased risk was also seen with benzocaine-based anesthetics, causing up to two-thirds of cases. 3,6 This has led to the recommendation that benzocaine should no longer be used and prilocaine should not be used in children younger than 6 months, in pregnant women, or in patients taking other oxidizing drugs. 6 Very rarely, methemoglobinemia maybe congenital in nature due to NADH reductase resulting in the inability to reduce ferric to ferrous iron (Fe3+ to Fe2+). 7 Congenital methemoglobinemia due to cytochrome b5 reductase deficiency is also very rare, but the actual incidence is not known. Increased frequency of congenital methemoglobinemia has been found in Siberian Yakuts, Athabaskans, Eskimos, and Navajo. 2

Clinical Presentation:
Patients with methemoglobinemia may represent with a variety of symptoms depending on the amount of methemoglobinemia in the blood. In less severe cases, patients may present with cyanosis. As levels progress, additional symptoms develop including anxiety, lightheadedness, headache, tachycardia, fatigue, confusion, dizziness, tachypnea, arrhythmias, seizures, and coma. 4 Patients may also develop lactic acidosis and myocardial ischemia. For 19 this reason, learners should obtain labs including CBC, CMP, venous blood gas or ABG if possible. ECG should also be obtained to look for signs of ischemia.

DEBRIEFING AND EVALUATION PEARLS
Methemoglobinemia is a clinical diagnosis based on history and presenting symptoms including hypoxemia refractory to supplementary oxygen. 1 Diagnosing methemoglobinemia requires high index of suspicion. Failure for the patient to respond appropriately to BiPAP and other supplementary oxygen should allow learners to explore other options. Co-oximetry may be obtained, which will reveal elevated levels of methemoglobin. The existence of an underlying heart, lung, or blood disease may exacerbate the toxicity of methemoglobinemia. 4 Obtaining a past medical history can be very vital in this case because it may guide them towards methemoglobinemia.

Treatment/Management:
• First step of management is to reduce exposure to known toxin if actively present.
• High-flow oxygen, nonrebreather, and BiPAP may improve symptoms, but pulse oximeter reading will remain unchanged. • Methylene blue should be given upon recognizing methemoglobinemia. Correct dosing is 1-2mg/kg IV over 5 minutes. This dose may be repeated if patient does not improve within 30 minutes. 4 o In patients with contraindication for methylene blue, such as G6PD deficiency, moderate amounts of vitamin C, 300-1000mg/day orally, may be used in divided doses. If ineffective, exchange transfusion may be completed. • Dextrose can also be given. This is due to the catabolism of sugar being a major source of NADH in the RBC. For reducing enzymes to be effective, glucose must be available in adequate supply. Dextrose is also necessary to form NADPH, which is necessary for methylene blue to be effective. Specific data about the amounts of dextrose to be given are not available but the recommendation is to give maintenance amounts in normoglycemia patients and standard dextrose therapy should be given to hypoglycemic patients. 4 • Hyperbaric Oxygenation Monotherapy has been successfully used before and may be used if patient fails methylene blue, or they are contraindicated. 8 • IV fluids should also be given along with bicarbonate in cases of metabolic acidosis. 5

Other debriefing points:
• Discuss evaluation and treatment of methemoglobinemia • Emphasize the importance of obtaining relevant past medical/surgical history